TGF beta signaling pathway

TGF beta signaling pathway

The Transforming growth factor beta (TGF) signaling pathway is involved in many cellular processes in both
the adult organism and the developing embryo including cell growth, cell differentiation, apoptosis, cellular
homeostasis and other cellular functions. In spite of the wide range of cellular processes that the TGF signaling
pathway regulates, the process is relatively simple. TGF superfamily ligands bind to a type II receptor, which
recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs
(R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus
where they act as transcription factors and participate in the regulation of target gene expression.

Mechanism
Ligand Binding
The TGF Beta superfamily of ligands include: Bone morphogenetic proteins
(BMPs), Growth and differentiation factors (GDFs), Anti-mllerian hormone
(AMH), Activin, Nodal and TGF's[1] . Signalling begins with the binding of
a TGF beta superfamily ligand to a TGF beta type II receptor. The type II
receptor is a serine/threonine receptor kinase, which catalyses the
phosphorylation of the Type I receptor. Each class of ligand binds to a
specific type II receptor[2] .In mammals there are seven known type I
receptors and five type II receptors[3] .
There are three activins: Activin A, Activin B and Activin AB. Activins are
involved in embryogenesis and osteogenesis. They also regulate many
hormones including pituitary, gonadal and hypothalamic hormones as well as
insulin. They are also nerve cell survival factors.
The BMPs bind to the Bone morphogenetic protein receptor type-2 (BMPR2).
They are involved in a multitude of cellular functions including osteogenesis,
cell differentiation, anterior/posterior axis specification, growth, and
homeostasis.
The TGF beta family include: TGF1, TGF2, TGF3. Like the BMPS, TGF
betas are involved in embryogenesis and cell differentiation, but they are also
involved in apoptosis, as well as other functions. They bind to TGF-beta receptor type-2 (TGFBR2).
Nodal binds to activin A receptor, type IIB ACVR2B. It can then either form a receptor complex with activin A
receptor, type IB (ACVR1B) or with activin A receptor, type IC (ACVR1C)[3] .

TGF beta signaling pathway

Receptor recruitment and phosphorylation

The TGF beta ligand binds to a type II receptor dimer, which recruits a type I
receptor dimer forming a hetero-tetrameric complex with the ligand[4] . These
receptors are serine/threonine kinase receptors. They have a cysteine rich
extracellular domain, a transmembrane domain and a cytoplasmic
serine/threonine rich domain. The GS domain of the type I receptor consists
of a series of about thirty serine-glycine repeats[5] . The binding of a TGF
beta family ligand causes the rotation of the receptors so that their
cytoplasmic kinase domains are arranged in a catalytically favorable
orientation. The Type II receptor phosphorylates serine residues of the Type I
receptor, which activates the protein.

SMAD phosphorylation
There are five receptor regulated SMADs: SMAD1, SMAD2, SMAD3,
SMAD5, and SMAD9 (sometimes referred to as SMAD8). There are
essentially two intracellular pathways involving these R-SMADs. TGF beta's,
Activins, Nodals and some GDFs are mediated by SMAD2 and SMAD3,
while BMPs, AMH and a few GDFs are mediated by SMAD1, SMAD5 and
SMAD9. The binding of the R-SMAD to the type I receptor is mediated by a
zinc double finger FYVE domain containing protein. Two such proteins that
mediate the TGF beta pathway include SARA (The SMAD anchor for
receptor activation) and HGS (Hepatocyte growth factor-regulated tyrosine
kinase substrate).
SARA is present in an early endosome which, by clathrin-mediated
endocytosis, internalizes the receptor complex[6] . SARA recruits an
R-SMAD. SARA permits the binding of the R-SMAD to the L45 region of
the Type I receptor[7] . SARA orients the R-SMAD such that serine residue
on its C-terminus faces the catalytic region of the Type I receptor. The Type I
receptor phosphorylates the serine residue of the R-SMAD. Phosphorylation
induces a conformational change in the MH2 domain of the R-SMAD and its
subsequent dissociation from the receptor complex and SARA[8] .

TGF beta signaling pathway

CoSMAD binding
The phosphorylated RSMAD has a high affinity for a coSMAD (e.g.
SMAD4) and forms a complex with one. The phosphate group does not act as
a docking site for coSMAD, rather the phosphorylation opens up an amino
acid stretch allowing interaction.

Transcription
The phosphorylated RSMAD/coSMAD complex enters the nucleus where it
binds transcription promoters/cofactors and causes the transcription of DNA.
Bone morphogenetic proteins cause the transcription of mRNAs involved in
osteogenesis, neurogenesis, and ventral mesoderm specification.
TGF betas cause the transcription of mRNAs involved in apoptosis,
extracellular matrix neogenesis and immunosuppression. It is also involved in
G1 arrest in the cell cycle.
Activin causes the transcription of mRNAs involved in gonadal growth,
embryo differentiation and placenta formation.
Nodal causes the transcription of mRNAs involved in left and right axis
specification, and mesoderm and endoderm induction.

Pathway regulation
The TGF beta signaling pathway is involved in a wide range of cellular
process and subsequently is very heavily regulated. There are a variety of
mechanisms that the pathway is modulated both positively and negatively:
There are agonists for ligands and R-SMADs; there are decoy receptors; and
R-SMADs and receptors are ubiquitinated.

TGF beta signaling pathway

Ligand agonists/antagonists
Both chordin and noggin are antagonists of BMP's. They bind BMP's preventing the binding of the ligand to the
receptor. It has been demonstrated that Chordin and Noggin dorsalize mesoderm. They are both found in the dorsal
lip of Xenopus and convert otherwise epidermis specified tissue into neural tissue (see neurulation). Noggin plays a
key role in cartilage and bone patterning. Mice Noggin-/- have excess cartilage and lacked joint formation[9] .
Members of the DAN family of proteins also antagonize TGF beta family members. They include Cerberus, DAN,
and Gremlin. These proteins contain nine conserved cysteines which can form disulfide bridges. It is believed that
DAN antagonizes GDF5, GDF6 and GDF7.
Follistatin inhibits Activin, which it binds. It directly affects follicle-stimulating hormone (FSH) secretion. Follistatin
also is implicated in prostate cancers where mutations in its gene may preventing it from acting on activin which has
anti-proliferative properties[9] .
Lefty is a regulator of TGF and is involved in the axis patterning during embryogenesis. It is also a member of the
TGF superfamily of proteins. It is asymmetrically expressed in the left side of murine embryos and subsequently
plays a role in left-right specification. Lefty acts by preventing the phosphorylation of R-SMADs. It does so through
a constitutively active TGF type I receptor and through a process downstream of its activation[10] .
Drug-based antagonists have also been identified, such as SB431542[11] , which selectively inhibits ALK4, ALK5,
and ALK7.

Receptor regulation
The Transforming growth factor receptor 3 (TGFBR3) is the most abundant of the TGF- receptors yet[12] , it has no
known signaling domain[13] . It however may serve to enhance the binding of TGF beta ligands to TGF beta type II
receptors by binding TGF and presenting it to TGFBR2. One of the downstream targets of TGF signaling, GIPC,
binds to its PDZ domain, which prevents its proteosomal degradation, which subsequently increases TGF activity.
It may also serve as an inhibin coreceptor to ActivinRII[9] .
BMP and Activin membrane bound inhibitor (BAMBI), has a similar extracellular domain as type I receptors. It
lacks an intracellular serine/threonine protein kinase domain and hence is a pseudoreceptor. It binds to the type I
receptor preventing it from being activated. It serves as a negative regulator of TGF beta signaling and may limit
tgf-beta expression during embryogeneis. It requires BMP signaling for its expression
FKBP12 binds the GS region of the type I receptor preventing phosphorylation of the receptor by the type II
receptors. It is believed that FKBP12 and its homologs help to prevent type I receptor activation in the absence of a
ligands, since ligand binding causes its dissociation.

R-SMAD regulation
Role of inhibitory SMADs
There are two other SMADs which complete the SMAD family, the inhibitory SMADs (I-SMADS), SMAD6 and
SMAD7. They play a key role in the regulation of TGF beta signaling and are involved in negative feeback. Like
other SMADs they have an MH1 and an MH2 domain. SMAD7 competes with other R-SMADs with the Type I
receptor and prevents their phosphorylation[9] [14] . It resides in the nucleus and upon TGF beta receptor activation
translocates to the cytoplasm where it binds the type I receptor. SMAD6 binds SMAD4 preventing the binding of
other R-SMADs with the coSMAD. The levels of I-SMAD increase with TGF beta signaling suggesting that they are
downstream targets of TGF-beta signaling.

TGF beta signaling pathway

R-SMAD ubiquitination
The E3 ubiquitin-protein ligases SMURF1 and SMURF2 regulate the levels of SMADs. They accept ubiquitin from
a E2 conjugating enzyme where they transfer ubiquitin to the RSMADs which causes their ubiquitination and
subsequent proteosomal degradation. SMURF1 binds to SMAD1 and SMAD5 while SMURF2 binds SMAD1,
SMAD2, SMAD3, SMAD6 and SMAD7. It enhances the inhibitory action of SMAD7 while reducing the
transcriptional activities of SMAD2.

Summary table
TGF Beta superfamily
ligand

Type II
Receptor

Type I receptor

R-SMADs

Ligand inhibitors
coSMAD

Activin A

ACVR2A

ACVR1B (ALK4)

SMAD2 , SMAD3

SMAD4

GDF1

ACVR2A

ACVR1B (ALK4)

SMAD2 , SMAD3

SMAD4

GDF11

ACVR2B

ACVR1B (ALK4), TGFRI

(ALK5)

SMAD2 , SMAD3

SMAD4

BMPR2

BMPR1A (ALK3), BMPR1B

(ALK6)

SMAD1 SMAD5,
SMAD9

SMAD4

Noggin, Chordin,
DAN

Nodal

ACVR2B

ACVR1B (ALK4), ACVR1C

(ALK7)

SMAD2 , SMAD3

SMAD4

Lefty

TGFs

TGFRII

TGFRI (ALK5)

SMAD2 , SMAD3

SMAD4

LTBP1, THBS1,
Decorin

Bone morphogenetic
proteins

Follistatin

External links
Kyoto Encyclopedia of Genes and Genomes -TGF beta signaling pathway [15] map
Netpath - A curated resource of signal transduction pathways in humans

References
[1] "Prosite Documentation PDOC00223" (http:/ / www. expasy. org/ cgi-bin/ nicedoc. pl?PS00250). . Retrieved 2006-07-01.
[2] Alberts, Bruce; Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter (2002). Molecular Biology of the Cell. New York,
NY: Garland Science. ISBN0-8153-3218-1.
[3] Munir S, Xu G, Wu Y, Yang B, Lala PK, Peng C (July 2004). "Nodal and ALK7 inhibit proliferation and induce apoptosis in human
trophoblast cells" (http:/ / www. jbc. org/ cgi/ content/ full/ 279/ 30/ 31277). J. Biol. Chem. 279 (30): 3127786.
doi:10.1074/jbc.M400641200. PMID15150278. .
[4] Wrana JL, Attisano L, Crcamo J, et al. (December 1992). "TGF beta signals through a heteromeric protein kinase receptor complex" (http:/ /
linkinghub. elsevier. com/ retrieve/ pii/ 0092-8674(92)90395-S). Cell 71 (6): 100314. doi:10.1016/0092-8674(92)90395-S. PMID1333888. .
[5] "Pfam entry TGF_beta_GS" (http:/ / www. sanger. ac. uk/ cgi-bin/ Pfam/ getacc?PF08515). . Retrieved 2006-07-01.
[6] Runyan CE, Schnaper HW, Poncelet AC (March 2005). "The role of internalization in transforming growth factor beta1-induced Smad2
association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells". J. Biol. Chem. 280
(9): 83008. doi:10.1074/jbc.M407939200. PMID15613484.
[7] Moustakas A (September 2002). "Smad signalling network" (http:/ / jcs. biologists. org/ cgi/ content/ full/ 115/ 17/ 3355). J. Cell. Sci. 115 (Pt
17): 33556. PMID12154066. .
[8] Souchelnytskyi S, Rnnstrand L, Heldin CH, ten Dijke P (2001). "Phosphorylation of Smad signaling proteins by receptor serine/threonine
kinases". Methods Mol. Biol. 124: 10720. PMID11100470.
[9] Massagu J, Chen YG (March 2000). "Controlling TGF-beta signaling" (http:/ / intl. genesdev. org/ cgi/ content/ full/ 14/ 6/ 627#B65). Genes
Dev. 14 (6): 62744. PMID10733523. .
[10] Ulloa L, Tabibzadeh S (June 2001). "Lefty inhibits receptor-regulated Smad phosphorylation induced by the activated transforming growth
factor-beta receptor" (http:/ / www. jbc. org/ cgi/ content/ full/ 276/ 24/ 21397). J. Biol. Chem. 276 (24): 21397404.
doi:10.1074/jbc.M010783200. PMID11278746. .

TGF beta signaling pathway

[11] Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, Martin W, Fornwald J, Lehr R, Harling J, Gaster L, Callahan JF,
Olson BA (July 2002). "Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the
TGF-beta type I receptor kinase activity: SB-431542" (http:/ / molpharm. aspetjournals. org/ cgi/ content/ full/ 62/ 1/ 58). Mol Pharmacol. 62
(1): 5864. doi:10.1124/mol.62.1.58. PMID12065755. .
[12] Blobe GC, Liu X, Fang SJ, How T, Lodish HF (October 2001). "A novel mechanism for regulating transforming growth factor beta
(TGF-beta) signaling. Functional modulation of type III TGF-beta receptor expression through interaction with the PDZ domain protein,
GIPC" (http:/ / www. jbc. org/ cgi/ content/ full/ 276/ 43/ 39608). J. Biol. Chem. 276 (43): 3960817. doi:10.1074/jbc.M106831200.
PMID11546783. .
[13] Online 'Mendelian Inheritance in Man' (OMIM) TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE III; TGFBR3
-600742 (http:/ / www. ncbi. nlm. nih. gov/ omim/ 600742)
[14] Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S (August 2001). "Promoting bone morphogenetic protein signaling through
negative regulation of inhibitory Smads" (http:/ / www. pubmedcentral. nih. gov/ articlerender. fcgi?tool=pmcentrez& artid=149146). Embo J.
20 (15): 413242. doi:10.1093/emboj/20.15.4132. PMID11483516. PMC149146.
[15] http:/ / www. genome. ad. jp/ dbget-bin/ show_pathway?hsa04350+ 7040

Article Sources and Contributors

Article Sources and Contributors

TGF beta signaling pathway Source: http://en.wikipedia.org/w/index.php?oldid=372347271 Contributors: Arcadian, Biochemza, Boghog2, ClockworkSoul, Deepraine, GAThrawn22, Gnfnrf,
Itskkumaran, JWSchmidt, OAndersson, Peter Znamenskiy, Ph.eyes, Quichehsu, R'n'B, RDBrown, Radiopie, Rainer198, Rich Farmbrough, Rich257, Rjwilmsi, Safflle, Smasslab, Smirly,
SunCreator, Tinz, 19 anonymous edits

Image Sources, Licenses and Contributors

Image:TGFbeta Pathway 1.svg Source: http://en.wikipedia.org/w/index.php?title=File:TGFbeta_Pathway_1.svg License: Creative Commons Attribution 2.5 Contributors: Jerome Walker
Image:TGF beta pathway 2.svg Source: http://en.wikipedia.org/w/index.php?title=File:TGF_beta_pathway_2.svg License: Creative Commons Attribution 2.5 Contributors: Jerome Walker
Image:TGF beta pathway step3.svg Source: http://en.wikipedia.org/w/index.php?title=File:TGF_beta_pathway_step3.svg License: Creative Commons Attribution 2.5 Contributors: Jerome
Walker
Image:TGF beta Pathway step4.svg Source: http://en.wikipedia.org/w/index.php?title=File:TGF_beta_Pathway_step4.svg License: Creative Commons Attribution 2.5 Contributors: Jerome
Walker
Image:Pathwaystep5.svg Source: http://en.wikipedia.org/w/index.php?title=File:Pathwaystep5.svg License: Creative Commons Attribution 2.5 Contributors: Jerome Walker

License
Creative Commons Attribution-Share Alike 3.0 Unported
http:/ / creativecommons. org/ licenses/ by-sa/ 3. 0/